Regulated intramembrane proteolysis: emergent role in cell signalling pathways

2017 ◽  
Vol 45 (6) ◽  
pp. 1185-1202 ◽  
Author(s):  
Aonghus J. McCarthy ◽  
Caroline Coleman-Vaughan ◽  
Justin V. McCarthy
Keyword(s):  
Cell Signalling ◽  
Signalling Pathways ◽  
Tumour Necrosis Factor Receptor ◽  
Intramembrane Proteolysis ◽  
Receptor Signalling ◽  
Regulated Intramembrane Proteolysis ◽  
Specific Receptors ◽  
Membrane Bound

Receptor signalling events including those initiated following activation of cytokine and growth factor receptors and the well-characterised death receptors (tumour necrosis factor receptor, type 1, FasR and TRAIL-R1/2) are initiated at the cell surface through the recruitment and formation of intracellular multiprotein signalling complexes that activate divergent signalling pathways. Over the past decade, research studies reveal that many of these receptor-initiated signalling events involve the sequential proteolysis of specific receptors by membrane-bound proteases and the γ-secretase protease complexes. Proteolysis enables the liberation of soluble receptor ectodomains and the generation of intracellular receptor cytoplasmic domain fragments. The combined and sequential enzymatic activity has been defined as regulated intramembrane proteolysis and is now a fundamental signal transduction process involved in the termination or propagation of receptor signalling events. In this review, we discuss emerging evidence for a role of the γ-secretase protease complexes and regulated intramembrane proteolysis in cell- and immune-signalling pathways.

scholarly journals Identification of new enterosynes using prebiotics: roles of bioactive lipids and mu-opioid receptor signalling in humans and mice

Gut ◽  
2020 ◽  
pp. gutjnl-2019-320230
Author(s):  
Anne Abot ◽  
Eve Wemelle ◽  
Claire Laurens ◽  
Adrien Paquot ◽  
Nicolas Pomie ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Enteric Neurons ◽  
Signalling Pathways ◽  
Bioactive Lipids ◽  
Mu Opioid Receptors ◽  
Mu Opioid ◽  
Receptor Signalling ◽  
Pathological Conditions

ObjectiveThe enteric nervous system (ENS) plays a key role in controlling the gut-brain axis under normal and pathological conditions, such as type 2 diabetes. The discovery of intestinal actors, such as enterosynes, able to modulate the ENS-induced duodenal contraction is considered an innovative approach. Among all the intestinal factors, the understanding of the role of gut microbes in controlling glycaemia is still developed. We studied whether the modulation of gut microbiota by prebiotics could permit the identification of novel enterosynes.DesignWe measured the effects of prebiotics on the production of bioactive lipids in the intestine and tested the identified lipid on ENS-induced contraction and glucose metabolism. Then, we studied the signalling pathways involved and compared the results obtained in mice to human.ResultsWe found that modulating the gut microbiota with prebiotics modifies the actions of enteric neurons, thereby controlling duodenal contraction and subsequently attenuating hyperglycaemia in diabetic mice. We discovered that the signalling pathway involved in these effects depends on the synthesis of a bioactive lipid 12-hydroxyeicosatetraenoic acid (12-HETE) and the presence of mu-opioid receptors (MOR) on enteric neurons. Using pharmacological approaches, we demonstrated the key role of the MOR receptors and proliferator-activated receptor γ for the effects of 12-HETE. These findings are supported by human data showing a decreased expression of the proenkephalin and MOR messanger RNAs in the duodenum of patients with diabetic.ConclusionsUsing a prebiotic approach, we identified enkephalin and 12-HETE as new enterosynes with potential real beneficial and safety impact in diabetic human.

Insights from vaccinia virus into Toll-like receptor signalling proteins and their regulation by ubiquitin: role of IRAK-2

2008 ◽  
Vol 36 (3) ◽  
pp. 449-452 ◽  
Author(s):  
Andrew G. Bowie
Keyword(s):  
Vaccinia Virus ◽  
Interleukin 1 ◽  
Nuclear Factor Κb ◽  
Tumour Necrosis Factor Receptor ◽  
Relative Role ◽  
Toll Like Receptor ◽  
Turn On ◽  
Receptor Signalling ◽  
Necrosis Factor

TLRs (Toll-like receptors) are an important class of pathogen-sensing proteins, which signal the presence of a pathogen by activating transcription factors, such as NF-κB (nuclear factor κB). The TLR pathway to NF-κB activation involves multiple phosphorylation and ubiquitination events. Notably, TRAF-6 [TNF (tumour necrosis factor)-receptor-associated factor-6] Lys63 polyubiquitination is a critical step in the formation of signalling complexes, which turn on NF-κB. Here, the relative role of different IRAKs [IL-1 (interleukin 1)-receptor-associated kinases] in NF-κB activation is discussed. Further, I demonstrate how understanding one molecular mechanism whereby vaccinia virus inhibits NF-κB activation has led to a revealing of a key role for IRAK-2 in TRAF-6-mediated NF-κB activation.

scholarly journals Oxidative stress in marathon runners: interest of antioxidant supplementation

2006 ◽  
Vol 96 (S1) ◽  
pp. S31-S33 ◽  
Author(s):  
Mari-Carmen Gomez-Cabrera ◽  
Agustín Martínez ◽  
Gustavo Santangelo ◽  
Federico V. Pallardó ◽  
Juan Sastre ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Xanthine Oxidase ◽  
Cell Signalling ◽  
Reactive Oxygen ◽  
Peripheral Blood Lymphocytes ◽  
Signalling Pathways ◽  
Marathon Running ◽  
Oxygen Species ◽  
Marathon Runners

We have recently reported that xanthine oxidase is involved in the generation of free radicals in exhaustive exercise. Allopurinol, an inhibitor of xanthine oxidase, prevents it. The aim of the present work was to elucidate the role of exercise-derived reactive oxygen species in the cell signalling pathways involved in the adaptation to exercise in man. We have found that exercise causes an increase in the activity of plasma xanthine oxidase and an activation of NF-κB in peripheral blood lymphocytes after marathon running. This activation is dependent on free radical formation in exercise: treatment with allopurinol completely prevents it. In animal models, we previously showed that NF-κB activation induced by exhaustive physical exercise leads to an increase in the expression of superoxide dismutase, an enzyme involved in antioxidant defence. We report evidence in man that reactive oxygen species act as signals in exercise as decreasing their formation prevents activation of important signalling pathways which can cause useful adaptations in cells.

Role of different aberrant cell signalling pathways prevalent in acute lymphoblastic leukemia

Biologia ◽  
2014 ◽  
Vol 69 (9) ◽  
Author(s):  
Priya Gopal ◽  
Mausumi Paul ◽  
Santanu Paul
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Treatment Options ◽  
Cell Signalling ◽  
Signalling Pathways ◽  
Survival Ratio ◽  
Functional Abnormality ◽  
Important Progress ◽  
Made In

AbstractAcute lymphoblastic leukemia (ALL) is one of the major forms of leukemia that affects mostly adolescent individuals. The main cause of the development of ALL is not known though several important signal transduction pathways have been reported with functional abnormality in all the cases. Crucial signalling pathways reported in ALL include PI3K/Akt, Notch, Wnt, mTOR, JaK/Stat, etc. Over the past several decades important progress has been made in the management of ALL, however, relapses and post therapy survival ratio has not improved much. This brings the need for understanding the biology and mechanism involved in ALL occurrences and find new molecular targets for better treatment options and risk-adapted therapies to improve the outcome of ALL patients.

scholarly journals Phylogenetic evidence for the modular evolution of metazoan signalling pathways

2017 ◽  
Vol 372 (1713) ◽  
pp. 20150477 ◽  
Author(s):  
Leslie S. Babonis ◽  
Mark Q. Martindale
Keyword(s):  
Cell Signalling ◽  
Large Body ◽  
Morphological Diversity ◽  
Signalling Pathway ◽  
Signalling Pathways ◽  
Special Focus ◽  
Tissue Interactions ◽  
Modular Evolution ◽  
Membrane Bound ◽  
Evo Devo

Communication among cells was paramount to the evolutionary increase in cell type diversity and, ultimately, the origin of large body size. Across the diversity of Metazoa, there are only few conserved cell signalling pathways known to orchestrate the complex cell and tissue interactions regulating development; thus, modification to these few pathways has been responsible for generating diversity during the evolution of animals. Here, we summarize evidence for the origin and putative function of the intracellular, membrane-bound and secreted components of seven metazoan cell signalling pathways with a special focus on early branching metazoans (ctenophores, poriferans, placozoans and cnidarians) and basal unikonts (amoebozoans, fungi, filastereans and choanoflagellates). We highlight the modular incorporation of intra- and extracellular components in each signalling pathway and suggest that increases in the complexity of the extracellular matrix may have further promoted the modulation of cell signalling during metazoan evolution. Most importantly, this updated view of metazoan signalling pathways highlights the need for explicit study of canonical signalling pathway components in taxa that do not operate a complete signalling pathway. Studies like these are critical for developing a deeper understanding of the evolution of cell signalling. This article is part of the themed issue ‘Evo-devo in the genomics era, and the origins of morphological diversity’.

scholarly journals Role of RNA in Facilitating Gag/Gag-Pol Interaction

2002 ◽  
Vol 76 (8) ◽  
pp. 4131-4137 ◽  
Author(s):  
Ahmad Khorchid ◽  
Rabih Halwani ◽  
Mark A. Wainberg ◽  
Lawrence Kleiman
Keyword(s):  
Human Immunodeficiency Virus ◽  
Genomic Rna ◽  
Immunodeficiency Virus ◽  
Membrane Bound ◽  
Bulk Membrane ◽  
Triton X ◽  
Viral Genomic Rna ◽  
Hiv 1

ABSTRACT We have examined the influence of RNA upon the interaction of Gag-Pol with Gag during human immunodeficiency virus type 1 (HIV-1) assembly. COS7 cells were transfected with protease-negative HIV-1 proviral DNA, and Gag/Gag-Pol complexes were detected by coimmunoprecipitation with anti-integrase. In COS7 cells, Gag/Gag-Pol is found almost entirely in pelletable, membrane-bound complexes. Exposure of cells to 1% Triton X-100 releases Gag/Gag-Pol from bulk membrane, but the complexes remain pelletable. The role of RNA in facilitating the interaction between Gag and Gag-Pol was examined in these bulk membrane-free, pelletable complexes. The specific presence of viral genomic RNA is not required to maintain the Gag/Gag-Pol interaction, but some type of RNA is, since exposure to RNase destabilized the Gag/Gag-Pol complex. When present only in Gag, the nucleocapsid mutation R7R10K11S, which inhibits Gag binding to RNA, inhibits the formation of both Gag and Gag/Gag-Pol complexes. When present only in Gag-Pol, this mutation has no effect upon complex formation. This result indicates that Gag-Pol may not interact directly with RNA but rather requires RNA-facilitated Gag multimerization for its interaction with Gag.

Membrane proteases and tetraspanins

2011 ◽  
Vol 39 (2) ◽  
pp. 541-546 ◽  
Author(s):  
María Yáñez-Mó ◽  
Francisco Sánchez-Madrid ◽  
Carlos Cabañas
Keyword(s):  
Plasma Membrane ◽  
Cross Talk ◽  
Signalling Pathways ◽  
Local Concentration ◽  
Matrix Degradation ◽  
Adhesion Receptors ◽  
Intramembrane Proteolysis ◽  
Regulated Intramembrane Proteolysis ◽  
Protein Shedding ◽  
Internalization Rate

TEMs (tetraspanin-enriched microdomains) are specialized platforms in the plasma membrane that include adhesion receptors and enzymes. Insertion into TEMs dictates the local concentration of these molecules, regulates their internalization rate, their interaction and cross-talk with other receptors at the plasma membrane and provides links with certain signalling pathways. We focus on the associations described for tetraspanins with membrane proteases and their substrates, reviewing the emerging evidence in the literature that suggests that TEMs might be essential platforms for regulating protein shedding, RIP (regulated intramembrane proteolysis) and matrix degradation and assembly.

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